Wnt signalling has been shown to be important in cancer. Indeed, Wnt signalling is implicated in tumour promotion and cancer via genetic defects at numerous levels or stages in the pathway. This topic is reviewed in detail by Polakis (2000 Genes and Development vol 14 pages 1837-1851).
Adenomatous polyposis coli (APC) has a central role in the Wnt signalling pathway. APC is an important tumour suppressor whose function is lost in the majority of sporadic and hereditary colorectal cancers. Its best understood function is the downregulation of β-catenin, a key effector of the Wnt signalling pathway. Moreover, APC proteins also appear to have a separate function in maintaining cadherin mediated cell adhesion, and loss of this function could accelerate the transition of tumours to invasive malignancy.
APC is inactivated in more than 80% of all colorectal cancers. The APC gene is defective in familial adenomatous polyposis (FAP), a dominantly-inherited disease that predisposes to colorectal tumours. Inactivation of APC is also seen in most sporadic tumours, and is an early, and possibly initiating, event in tumorigenesis.
APC is a negative regulator of the Wnt signalling pathway. It binds to and promotes the downregulation of β-catenin, a key effector of this pathway. In cells in which this pathway is inactive, β-catenin is rapidly degraded, as a result of phosphorylation in its N-terminus afforded by the Axin destruction complex that also contains glycogen synthase kinase 3β. On Wnt signalling, β-catenin is stabilised and translocates to the nucleus where it binds to TCF/LEF factors to activate the transcription of Wnt target genes. These changes in transcription are thought to be the basis for tumorigenesis. Thus it is a problem to control the transcription of Wnt target genes, or to attenuate their expression.
Current evidence suggests that APC, like β-catenin, may also have a separate function in cellular adhesion. This evidence arose from work in Drosophila where the APC relative E-APC is associated with adherens junctions in epithelia and appears to affect cellular adhesion. Evidence is emerging that this also applies to human cells: the APC tumour suppressor is associated with adhesive lateral membranes in various polarised mammalian cells, and has been implicated in the exchange of β-catenin at adherens junctions and in cellular adhesion of colorectal cancer cells. These findings are potentially relevant with regard to tumor progression since loss of cadherin-mediated adhesion often accompanies the transition of benign tumours to invasive carcinomas. Thus, it is problem to promote or maintain cellular adhesion such as cadherin-mediated adhesion.
The most conserved domain of APC proteins is their N-terminal Armadillo Repeat Domain (ARD), a putative protein-interaction domain. The closest relatives of this domain are found in β-catenin and α-importin, the functions and structures of these ARDs are well known, including their precise molecular interactions with many of their functionally relevant ligands. By contrast, it is a problem in the art that the molecular function of the ARD of APC proteins is poorly understood, and although there have been reports of putative ligands, their functional relevance with regard to APC is still unclear or unknown.
The present invention seeks to overcome problem(s) associated with the prior art.